New Mechanisms and Targets of Subarachnoid Hemorrhage: A Focus on Mitochondria

2021 ◽  
Vol 19 ◽  
Author(s):  
Zeyu Zhang ◽  
Anke Zhang ◽  
Yibo Liu ◽  
Xiaoming Hu ◽  
Yuanjian Fang ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Mitochondrial Dynamics ◽  
Delayed Cerebral Ischemia ◽  
Early Brain Injury ◽  
Adverse Outcomes ◽  
Heavy Burden ◽  
Poor Outcomes ◽  
Spontaneous Subarachnoid Hemorrhage ◽  
Membrane Organelle

: Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes, and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (ΔΨm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets, and summarize the promising therapeutic strategies targeting mitochondria for SAH.

scholarly journals Spontaneous subarachnoid hemorrhage of unknown origin: hospital course and long-term clinical and angiographic follow-up

2015 ◽  
Vol 122 (3) ◽  
pp. 663-670 ◽  
Author(s):  
Ali M. Elhadi ◽  
Joseph M. Zabramski ◽  
Kaith K. Almefty ◽  
George A. C. Mendes ◽  
Peter Nakaji ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
External Ventricular Drain ◽  
Delayed Cerebral Ischemia ◽  
Unknown Origin ◽  
Unknown Etiology ◽  
Neurological Outcomes ◽  
Spontaneous Subarachnoid Hemorrhage

OBJECT Hemorrhagic origin is unidentifiable in 10%–20% of patients presenting with spontaneous subarachnoid hemorrhage (SAH). While the patients in such cases do well clinically, there is a lack of long-term angiographic followup. The authors of the present study evaluated the long-term clinical and angiographic follow-up of a patient cohort with SAH of unknown origin that had been enrolled in the Barrow Ruptured Aneurysm Trial (BRAT). METHODS The BRAT database was searched for patients with SAH of unknown origin despite having undergone two or more angiographic studies as well as MRI of the brain and cervical spine. Follow-up was available at 6 months and 1 and 3 years after treatment. Analysis included demographic details, clinical outcome (Glasgow Outcome Scale, modified Rankin Scale [mRS]), and repeat vascular imaging. RESULTS Subarachnoid hemorrhage of unknown etiology was identified in 57 (11.9%) of the 472 patients enrolled in the BRAT study between March 2003 and January 2007. The mean age for this group was 51 years, and 40 members (70%) of the group were female. Sixteen of 56 patients (28.6%) required placement of an external ventricular drain for hydrocephalus, and 4 of these subsequently required a ventriculoperitoneal shunt. Delayed cerebral ischemia occurred in 4 patients (7%), leading to stroke in one of them. There were no rebleeding events. Eleven patients were lost to followup, and one patient died of unrelated causes. At the 3-year follow-up, 4 (9.1%) of 44 patients had a poor outcome (mRS > 2), and neurovascular imaging, which was available in 33 patients, was negative. CONCLUSIONS Hydrocephalus and delayed cerebral ischemia, while infrequent, do occur in SAH of unknown origin. Long-term neurological outcomes are generally good. A thorough evaluation to rule out an etiology of hemorrhage is necessary; however, imaging beyond 6 weeks from ictus has little utility, and rebleeding is unexpected.

scholarly journals 20-HETE is Associated with Unfavorable Outcomes in Subarachnoid Hemorrhage Patients

2015 ◽  
Vol 35 (9) ◽  
pp. 1515-1522 ◽  
Author(s):  
Mark K Donnelly ◽  
Elizabeth A Crago ◽  
Yvette P Conley ◽  
Jeffery R Balzer ◽  
Dianxu Ren ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Medical Center ◽  
Delayed Cerebral Ischemia ◽  
University Of Pittsburgh ◽  
Potential Contributor ◽  
Csf Levels ◽  
Novel Target ◽  
Poor Outcomes

Emerging evidence has suggested that patients experiencing aneurysmal subarachnoid hemorrhage (aSAH) develop vascular dysregulation as a potential contributor to poor outcomes. Preclinical studies have implicated the novel microvascular constrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) in aSAH pathogenesis, yet the translational relevance of 20-HETE in patients with aSAH is largely unknown. The goal of this research was to determine the relationship between 20-HETE cerebrospinal fluid (CSF) levels, gene variants in 20-HETE synthesis, and acute/long-term aSAH outcomes. In all, 363 adult patients (age 18 to 75) with aSAH were prospectively recruited from the University of Pittsburgh Medical Center neurovascular Intensive Care Unit. Patients were genotyped for polymorphic variants and cytochrome P450 (CYP)-eicosanoid CSF levels were measured over 14 days. Outcomes included delayed cerebral ischemia (DCI), clinical neurologic deterioration (CND), and modified Rankin Scores (MRS) at 3 and 12 months. Patients with CND and unfavorable 3-month MRS had 2.2- and 2.7-fold higher mean 20-HETE CSF levels, respectively. Patients in high/moderate 20-HETE trajectory groups (35.7%) were 2.5-, 2.1-, 3.1-, 3.3-, and 2.1-fold more likely to have unfavorable MRS at 3 months, unfavorable MRS at 12 months, mortality at 3 months, mortality at 12 months, and CND, respectively. These results showed that 20-HETE is associated with acute and long-term outcomes and suggest that 20-HETE may be a novel target in aSAH.

scholarly journals Imaging predictors of outcome in acute spontaneous subarachnoid hemorrhage: a review of the literature

2018 ◽  
Vol 60 (2) ◽  
pp. 247-259 ◽  
Author(s):  
Isabel Fragata ◽  
Patrícia Canhão
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Early Brain Injury ◽  
High Morbidity ◽  
Predictors Of Outcome ◽  
Imaging Studies ◽  
Prediction Of Complications ◽  
Spontaneous Subarachnoid Hemorrhage ◽  
Very High

Spontaneous subarachnoid hemorrhage (SAH) accounts for about 5% of strokes, but has a very high morbidity and mortality. Many survivors are left with important cognitive impairment and are severely incapacitated. Prediction of complications such as vasospasm and delayed cerebral ischemia, and of clinical outcome after SAH, is challenging. Imaging studies are essential in the initial evaluation of SAH patients and are increasingly relevant in assessing for complications and prognosis. In this article, we reviewed the role of imaging studies in evaluating early brain injury and predicting complications as well as clinical and neuropsychological prognosis after acute SAH.

scholarly journals Long-term impairment of neurovascular coupling following experimental subarachnoid hemorrhage

2019 ◽  
Vol 40 (6) ◽  
pp. 1193-1202 ◽  
Author(s):  
Matilde Balbi ◽  
Max Jativa Vega ◽  
Athanasios Lourbopoulos ◽  
Nicole A Terpolilli ◽  
Nikolaus Plesnila
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Neurovascular Coupling ◽  
Early Brain Injury ◽  
Vessel Diameter ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Experimental Subarachnoid Hemorrhage

CO2-reactivity and neurovascular coupling are sequentially lost within the first 24 h after subarachnoid hemorrhage (SAH). Whether and when these impairments recover is not known. Therefore, we investigated the reactivity of pial and intraparenchymal vessels by in vivo two-photon microscopy one month after experimental SAH. C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. One month later, cerebral blood flow following CO2-challenge and forepaw stimulation was assessed by laser Doppler fluxmetry. Diameters of pial and intraparenchymal arterioles were quantified by in vivo two-photon microscopy. One month after SAH, pial and parenchymal vessels dilated in response to CO2. Neurovascular coupling was almost completely absent after SAH: vessel diameter did not change upon forepaw stimulation compared to a 20% increase in sham-operated mice. The current results demonstrate that neurovascular function differentially recovers after SAH: while CO2-reactivity normalizes within one month after SAH, neurovascular coupling is still absent. These findings show an acute and persistent loss of neurovascular coupling after SAH that may serve as a link between early brain injury and delayed cerebral ischemia, two distinct pathophysiological phenomena after SAH that were so far believed not to be directly related.

scholarly journals Endothelin-1 and Endothelin Receptor Gene Variants and Their Association With Negative Outcomes Following Aneurysmal Subarachnoid Hemorrhage

2012 ◽  
Vol 15 (4) ◽  
pp. 390-397 ◽  
Author(s):  
Matthew Gallek ◽  
Sheila Alexander ◽  
Elizabeth Crago ◽  
Paula Sherwood ◽  
Michael Horowitz ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Receptor Gene ◽  
Delayed Cerebral Ischemia ◽  
The United States ◽  
Endothelin 1 ◽  
Potent Vasoconstrictor ◽  
Poor Outcomes

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease that affects approximately 30,000 people a year in the United States. Delayed cerebral ischemia (DCI) and cerebral vasospasm (CV) are common complications after aSAH. In addition, aSAH patients have a high risk of poor long-term outcomes. Endothelin-1 (ET-1), a potent vasoconstrictor, or its two types of receptors, ET receptor A (ETA) and ET receptor B (ETB), may play a role in the pathogenesis of DCI and CV. Genetic variations within the ET-1, ETA, or ETBgenes may also account for variance observed in the outcomes of aSAH patients. The purpose of this study was to describe the distribution of the Lys198Asn polymorphism, a known functional SNP in the ET-1 gene, and tagging SNPs of the ET-1, ETA, and ETBgenes in individuals recovering from aSAH. This study also investigated the relationships among the ET polymorphisms, DCI, and global functional outcomes measured at 3 and 6 months after aSAH. Participants included individuals aged 18–75 years with a diagnosis of aSAH. There was a trend found between the variant allele of an ET-1 SNP (rs6912834) and angiographic vasospasm. There were also associations found between two ETBSNPs (rs9574124 and rs3027111) and poor outcomes as measured by the Glasgow Outcome scale at 3 months. These findings support the role of ET-1 and ETBin recovery following aSAH.

Abstract 192: The Relationship of Platelet-leukocyte Aggregates and Early Brain Injury After Subarachnoid Hemorrhage

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Jennifer A Frontera ◽  
Vladimir Katyshev ◽  
Thomas M McIntyre ◽  
Fatima A Sehba ◽  
Jonathan M Weimer ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Delayed Cerebral Ischemia ◽  
Early Brain Injury ◽  
Aneurysm Rupture ◽  
Acute Brain Injury ◽  
Unruptured Aneurysms ◽  
Major Predictor ◽  
A Prospective Study ◽  
And Control

Introduction: Acute brain injury incurred after aneurysm rupture in subarachnoid hemorrhage (SAH) is a major predictor of poor functional outcome. We hypothesize that platelet-leukocyte aggregates (PLA) form early after SAH and contribute to acute brain injury. Methods: A prospective study of antiplatelet-naive SAH patients and controls (patients with unruptured aneurysms undergoing repair) was conducted from 3/2014-3/2016. Platelet-monocyte, platelet-lymphocyte and platelet-neutrophil aggregates in whole blood were measured with and without exposure to a platelet agonist (Thrombin receptor activating peptide [TRAP]) using flow cytometry. PLA within 24h and averaged over 72h from ictus (prior to the onset of delayed cerebral ischemia/vasospasm) were compared between patients with mild (admission Hunt-Hess [HH] 1-3) versus severe early brain injury (EBI; HH 4-5). Results: We enrolled 60 SAH patients and 13 controls. PLA were significantly lower in those with severe EBI compared to those with mild EBI (Platelet-monocyte-aggregates 36% versus 53%, P=0.011; Platelet-neutrophil-aggregates 15.2 versus 23.1%, P=0.002) within 24h of ictus and prior to aneurysm repair and remained significantly lower over 72h (both P<0.05). Platelet-monocyte, platelet-neutrophil and platelet-lymphocyte aggregates were also significantly lower in those with severe EBI compared to controls (all P<0.05). The ability of platelets to be stimulated/activated by TRAP to form PLA was also lower in severe EBI patients compared to mild EBI and control patients over 72h (platelet-neutrophil-aggregates 79.7, 88.2 and 92.7%, respectively, P=0.003; platelet-lymphocyte aggregates 9.2, 11.0 and 14.6%, respectively, P=0.022), consistent with prior platelet activation/degranulation. Conclusions: PLA are lower, and respond less to stimulation in patients with severe EBI after SAH compared to those with mild EBI and controls. These data suggest that in severe EBI: PLA may form earlier and are cleared, are adherent to endothelium and not shed in the blood, or have migrated into the parenchyma. These hypotheses bear further study.

Clinical complications and outcomes of angiographically negative subarachnoid hemorrhage

Neurology ◽  
2019 ◽  
Vol 92 (20) ◽  
pp. e2385-e2394 ◽  
Author(s):  
Cody L. Nesvick ◽  
Soliman Oushy ◽  
Lorenzo Rinaldo ◽  
Eelco F. Wijdicks ◽  
Giuseppe Lanzino ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Confidence Interval ◽  
Ventriculoperitoneal Shunt ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Tertiary Referral Center ◽  
Short And Long Term ◽  
Csf Diversion

ObjectiveTo define the in-hospital course, complications, short- and long-term functional outcomes of patients with angiographically negative subarachnoid hemorrhage (anSAH), particularly those with aneurysmal-pattern anSAH (aanSAH).MethodsRetrospective cohort study of patients with aneurysmal subarachnoid hemorrhage (aSAH), aanSAH, and perimesencephalic-pattern anSAH (panSAH) treated at a single tertiary referral center between January 2006 and April 2018. Ninety-nine patients with anSAH (33 aanSAH and 66 panSAH) and 464 patients with aSAH were included in this study. Outcomes included symptomatic hydrocephalus requiring CSF drainage, need for ventriculoperitoneal shunt, radiographic vasospasm, delayed cerebral ischemia (DCI), radiographic infarction, disability level within 1 year of ictus, and at last clinical follow-up as defined by the modified Rankin Scale.ResultsPatients with aanSAH and panSAH had similar rates of DCI and radiologic infarction, and patients with aanSAH had significantly lower rates compared to aSAH (p ≤ 0.018). Patients with aanSAH were more likely than those with panSAH to require temporary CSF diversion and ventriculoperitoneal shunt (p ≤ 0.03), with similar rates to those seen in aSAH. Only one patient with anSAH died in the hospital. Compared to those with aSAH, patients with aanSAH were significantly less likely to have a poor functional outcome within 1 year of ictus (odds ratio 0.26, 95% confidence interval 0.090–0.75) and at last follow-up (hazard ratio 0.30, 95% confidence interval 0.19–0.49, p = 0.002).ConclusionsDCI is very uncommon in anSAH, but patients with aanSAH have a similar need for short- and long-term CSF diversion to patients with aSAH. Nevertheless, patients with aanSAH have significantly better short- and long-term outcomes.

scholarly journals Computed tomography perfusion as a predictor of delayed cerebral ischemia and functional outcome in spontaneous subarachnoid hemorrhage: A single center experience

2019 ◽  
Vol 32 (3) ◽  
pp. 179-188 ◽  
Author(s):  
Isabel Fragata ◽  
Marta Alves ◽  
Ana Luísa Papoila ◽  
Ana Paiva Nunes ◽  
Patrícia Ferreira ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Clinical Outcome ◽  
Cerebral Perfusion ◽  
Ct Perfusion ◽  
Mean Transit Time ◽  
Multivariable Analysis ◽  
Delayed Cerebral Ischemia ◽  
Spontaneous Subarachnoid Hemorrhage

Background Computed tomography (CT) perfusion has been studied as a tool to predict delayed cerebral ischemia (DCI) and clinical outcome in spontaneous subarachnoid hemorrhage (SAH). The purpose of the study was to determine whether quantitative CT perfusion performed within 72 hours after admission can predict the occurrence of DCI and clinical outcome as measured with a modified Rankin scale (mRS) at 3 months after ictus. Methods Cerebral perfusion was assessed in a prospective cohort of patients with acute SAH. CT perfusion parameters at <72 h post SAH were quantitatively measured in the main vascular territories and represented as whole-brain means. Spearman rank correlation coefficient and generalized additive regression models for binary outcome were used. Results A total of 66 patients underwent CT perfusion at <72 h. Poor clinical grade on admission was correlated with worse cerebral perfusion in all parameters. Multivariable analysis yielded an association of time to peak (TTP; odds ratio (OR) = 0.89; 95% confidence interval (CI): 0.77, 1.02; p = 0.083) with the occurrence of DCI. We also found an association of TTP values with poor outcome, with an 8% increase in the odds of mRS > 3 for each one second increase in TTP at admission (OR = 1.08; 95% CI: 1.00, 1.17; p = 0.061). Conclusions We identified an association of early TTP changes with DCI and poor clinical outcome. However, there were no associations with cerebral blood flow or mean transit time and DCI/clinical outcome. CT perfusion still remains to be validated as a tool in predicting outcome in SAH.

Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery

1991 ◽  
Vol 74 (1) ◽  
pp. 8-13 ◽  
Author(s):  
Juha Öhman ◽  
Antti Servo ◽  
Olli Heiskanen
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
Ct Scanning ◽  
Long Term Effects ◽  
Cerebral Infarcts ◽  
Double Blind ◽  
Content Type

✓ A total of 213 patients with verified aneurysmal subarachnoid hemorrhage (SAH) of Grades I to III (Hunt and Hess classification) were enrolled in a double-blind placebo-controlled trial to determine the effect of intravenous nimodipine on delayed ischemic deterioration and computerized tomography (CT)-visualized infarcts after SAH and surgery. The administration of the drug or matching placebo was started immediately after the radiological diagnosis of a ruptured aneurysm had been made. Of the 213 patients enrolled in the study, 58 were operated on early (within 72 hours after the bleed: Days 0 to 3), 69 were operated on subacutely (between Days 4 and 7), and 74 had late surgery (on Day 8 or later). Eleven patients died before surgery was undertaken and one was not operated on. A follow-up examination with CT scanning, performed 1 to 3 years after the SAH (mean 1.4 years), revealed no significant differences in the overall outcome between the groups. However, nimodipine treatment was associated with a significantly lower incidence of deaths caused by delayed cerebral ischemia (p = 0.01) and significantly lower occurrence of cerebral infarcts visualized by CT scanning in the whole population (p = 0.05), especially in patients without an associated intracerebral hemorrhage on admission CT scan (p = 0.03).

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